The Application Of ICG-based Multifunctional Iron Chelator In Disease Diagnosis And Treatment

In the past 50 years,natural sources or chemically synthesized iron chelators(such as deferoxamine(DFO))have been clinically widely used to treat iron overload diseases.However,most of the known iron chelators have defects such as single function,limited bioavailability,great toxic and side effects,which limits their clinical use.Therefore,the development of multifunctional iron chelating agents with excellent pharmacokinetic properties and good biocompatibility plays an important role in the field of biomedicine.The repositioning of clinical indocyanine green(ICG)molecules with metal chelating properties in the framework of sulfonic acid(R-HSO3)and Lewis base(-NH)groups as a multifunctional iron chelator may have great potential.The work of this paper is mainly to verify the feasibility of Fe3+ detection,Fe3+ removal or Fe3+delivery functions based on ICG-designed drugs.This paper can be summarized as the following five main contents:(1)In the first chapter,we summarized the current research status of the structure and function of iron chelators,and introduced the most mature and influential clinical applications of iron chelator.By summarizing and analyzing the relationship between the structure of the existing iron chelator and its pharmacokinetics,advantages and disadvantages in clinical use,we conceived to repurpose the clinical ICG molecule as Fe3+chelator for the relevant clinical diagnosis and treatment.(2)In Chapter 2,we first verified the efficacy of ICG to chelate ferric ions in situ for signal amplification to decrease the detection limit of liver iron concentration in mouse models and human subjects.Moreover,this method could be calibrated via atomic absorption spectrometry and biopsy.In addition,ICG could accurately distinguish only one type of deposited iron in a short time.This showed that there was a good linear relationship between change of relative T1 signal intensity and liver iron concentration.(3)In Chapter 3,in order to make full use of the optical properties of ICG itself,we then introduced lecithin(Leci)when using ICG.Leci would prevent the transmonomerization of ICG from serum albumin and control the aggregation orientation of ICG molecules,finally facilitating the formation of J-aggregates of ICG and leading to a unique spectral change at 890 nm.The system provided excellent sensitivity for predicting the degree of liver iron overload.(4)In Chapter 4,we verified the ability of the ICG/Leci as iron detection platform to mobilize and remove iron from liver iron overloaded model mice,and verified its integrated function of liver iron diagnosis and treatment.This system has better iron removal efficiency,pharmacokinetic properties and biological safety than the existing clinically commonly used DFO iron removal agents.(5)In Chapter 5,in order to further broaden the application of ICG as an iron chelator,we further prepared Fe3+-mediated ionic crosslinking self-assembly microbubbles-Fe3+/ICG@MB system,which was produced by single-step.This system overcame the key problem of insufficient production rate of ROS in the current sonodynamic therapy(SDT),and meet the demand for non-invasive methods to monitor the therapeutic effect in vivo.This system showed great potential for SDT treatment of deep tumors.